Synergistic effect of kaempferol and 5‑fluorouracil on the growth of colorectal cancer cells by regulating the PI3K/Akt signaling pathway.
Mol Med Rep. 2019 Jul ;20(1):728-734. Epub 2019 May 27. PMID: 31180555
Combination chemotherapy with chemosensitizers can exert synergistic therapeutic effects, reduce toxicity, and delay the induction of drug resistance. In the present study, the antitumor effects were investigated, and the possible underlying mechanisms of kaempferol combined with 5‑fluorouracil (5‑FU) in colorectal cancer cells were explored. HCT‑8 or HCT‑116 cells were treated with various concentrations of kaempferol and/or 5‑FU for the indicated time‑points. An MTT assay was used to determine cell viability, whereas the synergistic effects were assessed by calculating the combination indices of kaempferol and 5‑FU. Annexin V analysis and Hoechst staining were used to determine cell apoptosis. q‑PCR and western blotting were performed to determine the expression levels of Bax, Bcl‑2, thymidylate synthase (TS), PTEN, PI3K, AKT, and p‑AKT. The combination of kaempferol and 5‑FU was determined to be more effective in inhibiting cell viability than either of the agents alone. The inhibition of tumors in response to kaempferol and 5‑FU was associated with the reduction in proliferation ability and stimulation of apoptosis. The protein resultsindicated that kaempferol and 5‑FU could significantly upregulate the expression levels of Bax and downregulate the expression levels of Bcl‑2 and TS. Furthermore, the combination treatment greatly inhibited the activation of the PI3K/Akt pathway, suggesting the involvement of this pathway in the synergistic effects. The present study demonstrated that kaempferol has a synergistic effect with 5‑FU by inhibiting cell proliferation and inducing apoptosis in colorectal cancer cells via suppression of TS or attenuation of p‑Akt activation. The combination of kaempferol and 5‑FU may be used as an effective therapeutic strategy for colorectal cancer.